6-51830849-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138694.4(PKHD1):c.8302+12T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,609,244 control chromosomes in the GnomAD database, including 143,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16090 hom., cov: 32)

Exomes 𝑓: 0.41 ( 127005 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.317

Publications

12 publications found

Variant links:

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
polycystic kidney disease 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
Caroli disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 6-51830849-A-T is Benign according to our data. Variant chr6-51830849-A-T is described in ClinVar as Benign. ClinVar VariationId is 96429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.8302+12T>A		intron_variant	Intron 52 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.8302+12T>A		intron_variant	Intron 52 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4 link	c.8302+12T>A		intron_variant	Intron 52 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.444

AC:

67445

AN:

151822

Hom.:

16065

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.500

Gnomad AMR

AF:

0.338

Gnomad ASJ

AF:

0.563

Gnomad EAS

AF:

0.0830

Gnomad SAS

AF:

0.292

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.608

Gnomad NFE

AF:

0.427

Gnomad OTH

AF:

0.479

GnomAD2 exomes

AF:

0.375

AC:

94101

AN:

250980

AF XY:

0.378

show subpopulations

Gnomad AFR exome

AF:

0.590

Gnomad AMR exome

AF:

0.235

Gnomad ASJ exome

AF:

0.548

Gnomad EAS exome

AF:

0.0823

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.440

Gnomad OTH exome

AF:

0.424

GnomAD4 exome

AF:

0.409

AC:

596261

AN:

1457304

Hom.:

127005

Cov.:

AF XY:

0.407

AC XY:

294944

AN XY:

725232

show subpopulations

African (AFR)

AF:

0.600

AC:

20012

AN:

33326

American (AMR)

AF:

0.250

AC:

11142

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.553

AC:

14406

AN:

26050

East Asian (EAS)

AF:

0.0849

AC:

3365

AN:

39628

South Asian (SAS)

AF:

0.312

AC:

26928

AN:

86192

European-Finnish (FIN)

AF:

0.350

AC:

18653

AN:

53358

Middle Eastern (MID)

AF:

0.534

AC:

3073

AN:

5750

European-Non Finnish (NFE)

AF:

0.427

AC:

473386

AN:

1108194

Other (OTH)

AF:

0.420

AC:

25296

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

16934

33869

50803

67738

84672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14290

28580

42870

57160

71450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.444

AC:

67518

AN:

151940

Hom.:

16090

Cov.:

AF XY:

0.434

AC XY:

32257

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.587

AC:

24338

AN:

41458

American (AMR)

AF:

0.337

AC:

5141

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.563

AC:

1949

AN:

3464

East Asian (EAS)

AF:

0.0829

AC:

429

AN:

5178

South Asian (SAS)

AF:

0.295

AC:

1421

AN:

4818

European-Finnish (FIN)

AF:

0.344

AC:

3621

AN:

10526

Middle Eastern (MID)

AF:

0.616

AC:

181

AN:

294

European-Non Finnish (NFE)

AF:

0.427

AC:

28975

AN:

67928

Other (OTH)

AF:

0.477

AC:

1008

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1858

3715

5573

7430

9288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.443

Hom.:

2885

Bravo

AF:

0.456

Asia WGS

AF:

0.259

AC:

901

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

Apr 12, 2018

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease 4

Benign:2

Jun 19, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The c.8302+12T>A, p.? variant was identified in 38.61% of 46763 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided

Benign:1

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.89

(source)

DANN

Benign

0.45

PhyloP100

-0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over